Case Report Multifactorial Hypercalcemia and Literature Review...

Case ReportMultifactorial Hypercalcemia and Literature Review on PrimaryHyperparathyroidism Associated with Lymphoma

Jelena Maletkovic,1 Jennifer P. Isorena,2 Miguel Fernando Palma Diaz,3

Stanley G. Korenman,1 and Michael W. Yeh2

1 Department of Endocrinology, UCLA David Geffen School of Medicine, Los Angeles, CA 90095, USA2 Section of Endocrine Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA3Department of Pathology and Laboratory Medicine, UCLA David Geffen School of Medicine, Los Angeles, CA 90095, USA

Correspondence should be addressed to Jelena Maletkovic; [email protected]

Received 16 December 2013; Accepted 24 January 2014; Published 5 March 2014

Academic Editors: G. Aimaretti, C. Capella, and R. Swaminathan

Copyright © 2014 Jelena Maletkovic et al. This is an open access article distributed under the Creative Commons AttributionLicense, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properlycited.

The most common cause of hypercalcemia in hospitalized patients is malignancy. Primary hyperparathyroidism most commonlycauses hypercalcemia in the outpatient setting.These two account for over 90% of all cases of hypercalcemia. Hypercalcemia can bedivided into PTH-mediated and PTH-independent variants. Primary hyperparathyroidism, familial hypocalciuric hypercalcemia,familial hyperparathyroidism, and secondary hyperparathyroidism are PTHmediated. The most common PTH-independent typeof hypercalcemia is malignancy related. Several mechanisms lead to hypercalcemia in malignancy-direct osteolysis by metastaticdisease or, more commonly, production of humoral factors by the primary tumor also known as humoral hypercalcemia ofmalignancy that accounts for about 80% of malignancy-related hypercalcemia.Themajority of HHM is caused by tumor-producedparathyroid hormone-related protein and less frequently production of 1,25-dihydroxyvitamin D or parathyroid hormone by thetumor. We report the rare case of a patient with hypercalcemia and diagnosed primary hyperparathyroidism. The patient hadpersistent hypercalcemia after surgical removal of parathyroid adenoma with recorded significant decrease in PTH level. Aftercontinued investigation it was found that the patient also had elevated 1,25-dihydroxyvitamin D and further studies confirmed alarge spleen mass that was later confirmed to be a lymphoma. This is a rare example of two concomitant causes of hypercalcemiarequiring therapy.

1. Introduction

Hypercalcemia is defined as total serum calcium above10.5mg/dL (>2.6mmol/L). In a pregnant patient the upperlimit of normal is considered to be 9.5mg/dL [1]. The mostcommon cause of hypercalcemia in hospitalized patients ismalignancy. Primary hyperparathyroidism most commonlycauses hypercalcemia in the outpatient setting [2]. These twoaccount for over 90% of all cases of hypercalcemia.

Hypercalcemia can be divided into PTH-mediated andPTH-independent variants. Primary hyperparathyroidism(PHPT), familial hypocalciuric hypercalcemia, familialhyperparathyroidism, and secondary hyperparathyroidism

are PTHmediated. In these patients initial evaluation revealsincreased or inappropriately normal PTH (not suppressed inthe setting of hypercalcemia) which narrows the differentialdiagnosis. The most common PTH-independent type ofhypercalcemia is malignancy related. Several mechanismslead to hypercalcemia in malignancy-direct osteolysis bymetastatic disease or, more commonly, production ofhumoral factors by the primary tumor also known ashumoral hypercalcemia of malignancy (HHM) that accountsfor about 80% of malignancy-related hypercalcemia. Themajority of HHM is caused by tumor-produced parathyroidhormone-related protein (PTHrP) and, less frequently,production of 1,25-dihydroxyvitamin D (1,25D) or para-

Hindawi Publishing CorporationCase Reports in EndocrinologyVolume 2014, Article ID 893134, 4 pageshttp://dx.doi.org/10.1155/2014/893134

2 Case Reports in Endocrinology

Table 1: Pertinent labs before and after parathyroidectomy and resection of the spleen.

Lab On firstpresentation

Afterparathyroidectomy

Postop. day 1

AfterparathyroidectomyPostop. day 10

Aftersplenectomy

∼One year aftersplenectomy

Total calcium (mg/dL) 16.3 11.1 12.9 10.6 8.9PTH (pg/mL) 58 5 4 5 78Creatinine (mg/dL) 4.9 0.9 1.8 1.3 1.2925D (pg/mL) 22 19 19 18.5 371.25D (pg/mL) >220 133.6 62PTHrP (pmol/L) <2

Table 2: The literature review of reported cases of hypercalcemia and malignancy.

Study Basic study features Cause of hypercalcemia

Strodel et al. [9] 18 patients with malignancy and hypercalcemia All patients had PHPT as the only cause ofhypercalcemia.

Hutchesson et al. [10] 47 patients with malignancy and hypercalcemia3 of 47 patients had PHPT as the cause ofhypercalcemia. No cases of 2 causes of elevatedcalcium levels.

Owen et al. [11] 2 cases of primary cutaneous lymphomas andhypercalcemia

Both cases were found to have PHPT as the onlycause of hypercalcemia

Albes et al. [12] A case of T-cell lymphoma and hypercalcemia Hypercalcemia caused by PHPT onlyAguilar-Bernier et al.[13] Lymphomatoid papulosis Hypercalcemia caused by PHPT only

Gallacher et al. [14]

Hypercalcemia did not resolve after removal ofparathyroid adenoma which prompted furtherworkup and the patient was found to havemalignancy in the manubrium sterni

One case with two coexisting mechanisms ofhypercalcemia—PHPT and PTHrP mediated

Luceri and Haenel[15]

Hypercalcemia did not resolve after removal ofparathyroid adenoma which prompted furtherworkup and the patient was found to have diffuselarge B-cell lymphoma

One case with two coexisting mechanisms ofhypercalcemia—PHPT and 1,25-dihydroxyvitaminD mediated

Figure 1: Abdominal CT showing splenic mass.

thyroid hormone by the tumor [3]. Tumors secreting PTHrPcause increased bone resorption and distal renal tubularcalcium reabsorption. Tumors that cause elevation in 1,25Dcause hypercalcemia as a result of a combination of increasedbone resorption and intestinal calcium absorption.

Primary hyperparathyroidism with an adenoma orhyperplasia producing hypercalcemia is a relatively com-mon endocrine problem that is treated surgically. If the

hypercalcemia persists after resection of an adenoma, thenthe differential diagnosis would depend on whether thehypercalcemia is associated with a relatively high or a lowPTH. With a high PTH the surgeon needs to seek anotheradenoma or parathyroid hyperplasia. With a low PTH,hypercalcemia must depend on other causes that have to besought.

We report the rare case of a patient with two concomitantcauses of hypercalcemia requiring therapy.

2. Case

A previously healthy 67-year-old man was taken to theemergency room for polyuria, unsteady gait, dizziness, andconfusion. The patient was found to have a calcium levelof 16.3mg/dL (reference range 8.6–10.2) and acute renalfailure with a Cr of 4.9mg/dL. The PTH level was elevatedat 58 pg/mL (11–51 pg/mL). He was treated with IV fluids,calcitonin, and one dose of pamidronate. His serum calciumand creatinine improved. An ultrasound of the neck wasconsistent with a right inferior parathyroid mass that onsurgical removal was confirmed by histopathology to be aparathyroid adenoma. Intraoperatively his PTH fell from51 to

Case Reports in Endocrinology 3

(a) (b)

(c)

Figure 2: (a) H&E, 40x: sections of the spleen show a proliferation of highly atypical large lymphoid cells resulting in extensive effacement ofthe splenic architecture.The cells show irregular nuclei with open vesicular chromatin, prominent nucleoli, andmoderate to scant cytoplasm.Abundant mitotic figures are seen. (b) Immunohistochemistry, CD20, 40x: the neoplastic lymphoid cells exhibit diffuse and strong stainingfor CD20. (c) Immunohistochemistry, 1-alpha-hydroxylase, 40x: neoplastic lymphoid cells exhibit moderate, irregular immunoreactivity for1-alpha-hydroxylase in a cytoplasmic distribution.

10 pg/mL.The serum calcium at 11.1mg/dL did not normalizefollowing the surgery.

His creatinine became normal and the PTH remained lowat 5 pg/mL. Workup for persistent hypercalcemia revealeda normal PTHrP and a high 1,25-dihydroxyvitamin D of>200 pg/mL (reference range: 15–75) indicating the addi-tional mechanism of hypercalcemia (Table 1).

His previous workup was negative for sarcoidosis andmultiple myeloma and he never took any vitamin D orcalcium supplements. An abdominal CT scan showed asplenic mass (Figure 1).

Following the resection of this mass the calcium levelnormalized. The mass was found to be a diffuse large B-cell lymphoma. Immunohistochemistry showed that neo-plastic lymphoid cells exhibit strong staining for CD20. Mostimportantly, from the hypercalcemia perspective, it showsimmunoreactivity for 1-alpha-hydroxylase in a cytoplasmicdistribution (Figures 2(a), 2(b), and 2(c)).

3. Discussion

Hypercalcemia is a relatively frequent complication of lym-phoma [4]. Increased circulating levels of 1,25D have beendescribed in patients withHodgkin’s and non-Hodgkin’s lym-phomas [5, 6]. Calcidiol (25-hydroxyvitamin D) is metabol-ically activated in the proximal convoluted tubule cells of

the kidney to produce calcitriol (1,25D) by 1-alpha hydrox-ylase. This reaction is stimulated by PTH, calcitonin, andhypophosphatemia and inhibited by calcium, 1,25D, andhyperphosphatemia [7]. 1-Alpha-hydroxylase belongs to thecytochrome p450 superfamily of enzymes and is encoded bythe CYP27B1 gene.

Hewison and colleagues used immunohistochemistry todemonstrate the presence of 1𝛼-hydroxylase in macrophagesassociated with lymphomas. They suggested that the tumorsecreted factors that stimulated 1𝛼-hydroxylase expression bymacrophages [8].

Some studies have claimed that 15% of patients withhypercalcemia and malignancy have coexisting hyperpara-thyroidism (Table 2). A report by Strodel et al. in 1988shows a group of 18 patients with malignant tumors andhypercalcemia caused by PHPT. In all cases, serum levelsof calcium returned to normal after surgical removal ofa parathyroid adenoma or hyperplasia indicating that thehypercalcemia was caused by only one mechanism [9].Hutchesson et al. report 47 patients with hypercalcemiaand malignancy; however, in three patients it was foundthat hypercalcemia was caused by PHPT and hypercalcemiaresolved after surgical removal of a parathyroid adenoma[10]. Owen et al. report 2 cases of parathyroid adenoma inpatients with primary cutaneous lymphomas [11]. In bothcases serum calcium levels returned to normal after removalof the parathyroid adenoma. Neither PTHrP nor 1,25D levels

4 Case Reports in Endocrinology

were assessed. Two additional isolated cases of parathyroidadenoma causing hypercalcemia in patients with T-cell lym-phoma [12] and lymphomatoid papulosis [13] were reportedsubsequently.

In all but two reports the hypercalcemia was causedby only one mechanism. A patient of Gallacher et al. wasfound to have persistent hypercalcemia after a parathyroidadenoma was removed and PTH levels fell, leading to furtherinvestigation that revealed elevated PTHrP and a carcinomain the manubrium [14]. The humoral mechanism via PTHrP,however, was different than our patient’s who had 1,25Delevation. The only report to our knowledge of coexistingPHPT and diffuse large B-cell lymphoma causing 1,25Delevation and multifactorial hypercalcemia was published in2013 by Luceri and Haenel IV [15].

Two distinct causes of hypercalcemia may coexist bychance. Some authors have also suggested that hyperparathy-roidism may be associated with the slight increase in theincidence of malignancy [16]. At this time we do not knowwhether there is any relation between lymphoma and PHPT.

Persistence of hypercalcemia after removal of the causallesion should prompt a thorough workup for another sourcebased on whether the offending agent is PTH, PTHrP, orVitamin D.

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper.

References

[1] E. Holt, “Calcium physiology in pregnancy,” 2013, http://wwwuptodate.com.

[2] W. A. Ratcliffe, A. C. J. Hutchesson, N. J. Bundred, and J.G. Ratcliffe, “Role of assays for parathyroid-hormone-relatedprotein in investigation of hypercalcaemia,”TheLancet, vol. 339,no. 8786, pp. 164–167, 1991.

[3] G. A. Clines, “Mechanisms and treatment of hypercalcemia ofmalignancy,” Current Opinion in Endocrinology, Diabetes andObesity, vol. 18, no. 6, pp. 339–346, 2011.

[4] M. Burt and M. F. Brennan, “Incidence of hypercalcemia andmalignant neoplasm,” Archives of Surgery, vol. 115, no. 6, pp.704–707, 1980.

[5] J. F. Seymour and R. F. Gagel, “Calcitriol: the major humoralmediator of hypercalcemia in Hodgkin’s disease and non-Hodgkin’s lymphomas,”Blood, vol. 82, no. 5, pp. 1383–1394, 1993.

[6] J. F. Seymour, R. F. Gagel, F. B. Hagemeister, M. A. Dimopoulos,and F. Cabanillas, “Calcitriol production in hypercalcemic andnormocalcemic patientswith non-Hodgkin lymphoma,”Annalsof Internal Medicine, vol. 121, no. 9, pp. 633–640, 1994.

[7] R. Bland, D. Zehnder, and M. Hewison, “Expression of 25-hydroxyvitamin D3-1𝛼-hydroxylase along the nephron: newinsights into renal vitamin D metabolism,” Current Opinion inNephrology and Hypertension, vol. 9, no. 1, pp. 17–22, 2000.

[8] M. Hewison, V. Kantorovich, H. R. Liker et al., “Vitamin D-mediated hypercalcemia in lymphoma: evidence for hormoneproduction by tumor-adjacent macrophages,” Journal of Boneand Mineral Research, vol. 18, no. 3, pp. 579–582, 2003.

[9] W. E. Strodel, N. W.Thompson, F. E. Eckhauser, and J. A. Knol,“Malignancy and concomitant primary hyperparathyroidism,”Journal of Surgical Oncology, vol. 37, no. 1, pp. 10–12, 1988.

[10] A. C. J. Hutchesson, N. J. Bundred, andW.A. Ratcliffe, “Survivalin hypercalcaemic patients with cancer and co-existing primaryhyperparathyroidism,” PostgraduateMedical Journal, vol. 71, no.831, pp. 28–31, 1995.

[11] C.M.Owen, R.W. Blewitt, P. V. Harrison, andV.M. Yates, “Twocases of primary hyperparathyroidism associated with primarycutaneous lymphoma,” British Journal of Dermatology, vol. 142,no. 1, pp. 120–123, 2000.

[12] B. Albes, J. Bazex, P. Bayle-Lebey, A. Bennet, and L. Lamant,“Primary hyperparathyroidism and cutaneous T-cell lym-phoma: fortuitous association?”Dermatology, vol. 203, no. 2, pp.162–164, 2001.

[13] M. Aguilar-Bernier, J. Bassas-Vila, M. T. Bordel-Gomez, A.Morales-Callaghan, J. A. Tejerina-Garcia, and A. Miranda-Romero, “Lymphomatoid papulosis associatedwith parathyroidnodular hyperplasia: report of a case,” Journal of the EuropeanAcademy ofDermatology andVenereology, vol. 18, no. 6, pp. 693–696, 2004.

[14] S. J. Gallacher, W. D. Fraser, M. A. Farquharson et al., “Coinci-dental occurrence of primary hyperparathyroidism and cancer-associated hypercalcaemia in a middle-aged man,” ClinicalEndocrinology, vol. 38, no. 4, pp. 433–437, 1993.

[15] P. M. Luceri and L. C. Haenel IV, “A challenging case of hyper-calcemia,”The Journal of the American Osteopathic Association,vol. 113, no. 6, pp. 490–493, 2013.

[16] D. A. Heath, “Primary hyperparathyroidism: clinical presenta-tion and factors influencing clinical management,” Endocrinol-ogy and Metabolism Clinics of North America, vol. 18, no. 3, pp.631–646, 1989.

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